The unifying goal of this program project is to define the principles governing normal nervous system developmental processes that may lead to brain dysfunction and mental retardation. The studies for the most part are basic in nature, focusing on various aspects of the cell and its environment that are involved in overall developmental processes; including examination of the extracellular matrix (ECM), cell membrane gap junctions, organogenesis, and intracellular modifying enzymes which provide the milieu for cell differentiation and proliferation. The derivative information from these proposed studies should define specific loci where normal developmental processes may be interrupted leading to abnormal nervous system development and mental retardation. Project I focuses on the structure and function of brain proteoglycans, with emphasis on control of expression of one of the major chondroitin sulfate proteoglycans (aggrecan) and elucidation of the role this important ECM component plays in neuronal development. Project II will examine the roles of intercellular communication and connexin expression in the patterning and segmentation of the developing hindbrain and spinal cord. Project III focuses on the molecular pathways that are responsible for pineal gland organogenesis by assessing the roles of BMPs and homeobox genes in the initial stages of pineal development and to place them within a molecular pathway. Project IV is aimed toward understanding the pathogenesis of the late infantile form of Batten disease, by using gene transfection and specific inhibitors to implicate lipid-rich microdomains as the site of action of the CLN1 gene product. Mutations in the CLN1 gene lead to a deficiency of palmitoyl: protein thioesterase, resulting in the premature death of neurons and mental retardation. A comprehensive multi-disciplinary approach using biochemical, molecular, genetic, morphologic and cell culture techniques will be used in all four projects. There is overall emphasis on gene transfection modalities and molecular expression analysis using in situ hybridization and in ovo electroporation to study embryonic brain development. [unreadable] [unreadable]